The effects of atrasentan on urinary metabolites in patients with type 2 diabetes and nephropathy

Michelle J. Pena, Dick de Zeeuw, Dennis Andress, John J. Brennan, Ricardo Correa-Rotter, Blai Coll, Donald E. Kohan, Hirofumi Makino, Vlado Perkovic, Giuseppe Remuzzi, Sheldon W. Tobe, Robert Toto, Hans Henrik Parving, Shoba Sharma, Tom Corringham, Kumar Sharma, Hiddo J.L. Heerspink

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6 Citations (Scopus)

Abstract

We assessed the effect of atrasentan therapy on a pre-specified panel of 13 urinary metabolites known to reflect mitochondrial function in patients with diabetic kidney disease. This post-hoc analysis was performed using urine samples collected during the RADAR study which was a randomized, double-blind, placebo-controlled trial that tested the effects of atrasentan on albuminuria reduction in patients with type 2 diabetes and nephropathy. At baseline, 4 of the 13 metabolites, quantified by gas-chromatography mass spectrometry, were below detectable levels, and 6 were reduced in patients with eGFR < 60 mL/min/1.73 m2. After 12 weeks of atrasentan treatment in patients with eGFR < 60 mL/min/1.73 m2, a single-value index of the metabolites changed by −0.31 (95%CI −0.60 to −0.02; P =.035), −0.08 (−12 to 0.29; P =.43) and 0.01 (−0.21 to 0.19; P =.913) in placebo, atrasentan 0.75 and 1.25 mg/d, respectively. The metabolite index difference compared to placebo was 0.13 (−0.17 to 0.43; P =.40) and 0.35 (0.05-0.65; P =.02) for atrasentan 0.75 and 1.25 mg/d, respectively. These data corroborate previous findings of mitochondrial dysfunction in patients with type 2 diabetes, nephropathy and eGFR < 60 mL/min/1.73 m2, suggesting that atrasentan may prevent the progression of mitochondrial dysfunction common to this specific patient population. Future studies of longer treatment duration with atrasentan are indicated.

Original languageEnglish
Pages (from-to)749-753
Number of pages5
JournalDiabetes, Obesity and Metabolism
Volume19
Issue number5
DOIs
Publication statusPublished - May 2017

Keywords

  • diabetic kidney disease
  • eGFR decline
  • metabolomics

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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    Pena, M. J., de Zeeuw, D., Andress, D., Brennan, J. J., Correa-Rotter, R., Coll, B., Kohan, D. E., Makino, H., Perkovic, V., Remuzzi, G., Tobe, S. W., Toto, R., Parving, H. H., Sharma, S., Corringham, T., Sharma, K., & Heerspink, H. J. L. (2017). The effects of atrasentan on urinary metabolites in patients with type 2 diabetes and nephropathy. Diabetes, Obesity and Metabolism, 19(5), 749-753. https://doi.org/10.1111/dom.12864